Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly

Daniela A. Braun, Jia Rao, Geraldine Mollet, David Schapiro, Marie Claire Daugeron, Weizhen Tan, Olivier Gribouval, Olivia Boyer, Patrick Revy, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Jennifer A. Lawson, Denny Schanze, Shazia Ashraf, Jeremy F.P. Ullmann, Charlotte A. Hoogstraten, Nathalie Boddaert, Bruno Collinet, Gaelle Martin, Dominique LigerSvjetlana Lovric, Monica Furlano, I. Chiara Guerrera, Oraly Sanchez-Ferras, Jennifer F. Hu, Anne Claire Boschat, Sylvia Sanquer, Björn Menten, Sarah Vergult, Nina De Rocker, Merlin Airik, Tobias Hermle, Shirlee Shril, Eugen Widmeier, Heon Yung Gee, Won Il Choi, Carolin E. Sadowski, Werner L. Pabst, Jillian K. Warejko, Ankana Daga, Tamara Basta, Verena Matejas, Karin Scharmann, Sandra D. Kienast, Babak Behnam, Brendan Beeson, Amber Begtrup, Malcolm Bruce, Gaik Siew Ch'Ng, Shuan Pei Lin, Jui Hsing Chang, Chao Huei Chen, Megan T. Cho, Patrick M. Gaffney, Patrick E. Gipson, Chyong Hsin Hsu, Jameela A. Kari, Yu Yuan Ke, Cathy Kiraly-Borri, Wai Ming Lai, Emmanuelle Lemyre, Rebecca Okashah Littlejohn, Amira Masri, Mastaneh Moghtaderi, Kazuyuki Nakamura, Fatih Ozaltin, Marleen Praet, Chitra Prasad, Agnieszka Prytula, Elizabeth R. Roeder, Patrick Rump, Rhonda E. Schnur, Takashi Shiihara, Manish D. Sinha, Neveen A. Soliman, Kenza Soulami, David A. Sweetser, Wen Hui Tsai, Jeng Daw Tsai, Rezan Topaloglu, Udo Vester, David H. Viskochil, Nithiwat Vatanavicharn, Jessica L. Waxler, Klaas J. Wierenga, Matthias T.F. Wolf, Sik Nin Wong, Sebastian A. Leidel, Gessica Truglio, Peter C. Dedon, Annapurna Poduri, Shrikant Mane, Richard P. Lifton, Maxime Bouchard, Peter Kannu, David Chitayat, Daniella Magen, Bert Callewaert, Herman Van Tilbeurgh, Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Galloway-Mowat syndrome (GAMOS) is an autosomalrecessive disease characterized by the combination of earlyonset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Original languageEnglish (US)
Pages (from-to)1529-1538
Number of pages10
JournalNature Genetics
Volume49
Issue number10
DOIs
StatePublished - Oct 1 2017

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Microcephaly
Kidney
Mutation
Genes
Clustered Regularly Interspaced Short Palindromic Repeats
Phenotype
Podocytes
Endoplasmic Reticulum Stress
Nephrotic Syndrome
Protein Biosynthesis
Zebrafish
Actin Cytoskeleton
DNA Damage
Cell Proliferation
Apoptosis
Brain
Galloway Mowat syndrome
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Braun, D. A., Rao, J., Mollet, G., Schapiro, D., Daugeron, M. C., Tan, W., ... Hildebrandt, F. (2017). Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly. Nature Genetics, 49(10), 1529-1538. https://doi.org/10.1038/ng.3933

Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly. / Braun, Daniela A.; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A.; Schanze, Denny; Ashraf, Shazia; Ullmann, Jeremy F.P.; Hoogstraten, Charlotte A.; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaelle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I. Chiara; Sanchez-Ferras, Oraly; Hu, Jennifer F.; Boschat, Anne Claire; Sanquer, Sylvia; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Yung Gee, Heon; Choi, Won Il; Sadowski, Carolin E.; Pabst, Werner L.; Warejko, Jillian K.; Daga, Ankana; Basta, Tamara; Matejas, Verena; Scharmann, Karin; Kienast, Sandra D.; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'Ng, Gaik Siew; Lin, Shuan Pei; Chang, Jui Hsing; Chen, Chao Huei; Cho, Megan T.; Gaffney, Patrick M.; Gipson, Patrick E.; Hsu, Chyong Hsin; Kari, Jameela A.; Ke, Yu Yuan; Kiraly-Borri, Cathy; Lai, Wai Ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okashah; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Ozaltin, Fatih; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth R.; Rump, Patrick; Schnur, Rhonda E.; Shiihara, Takashi; Sinha, Manish D.; Soliman, Neveen A.; Soulami, Kenza; Sweetser, David A.; Tsai, Wen Hui; Tsai, Jeng Daw; Topaloglu, Rezan; Vester, Udo; Viskochil, David H.; Vatanavicharn, Nithiwat; Waxler, Jessica L.; Wierenga, Klaas J.; Wolf, Matthias T.F.; Wong, Sik Nin; Leidel, Sebastian A.; Truglio, Gessica; Dedon, Peter C.; Poduri, Annapurna; Mane, Shrikant; Lifton, Richard P.; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Callewaert, Bert; Van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm.

In: Nature Genetics, Vol. 49, No. 10, 01.10.2017, p. 1529-1538.

Research output: Contribution to journalArticle

Braun, DA, Rao, J, Mollet, G, Schapiro, D, Daugeron, MC, Tan, W, Gribouval, O, Boyer, O, Revy, P, Jobst-Schwan, T, Schmidt, JM, Lawson, JA, Schanze, D, Ashraf, S, Ullmann, JFP, Hoogstraten, CA, Boddaert, N, Collinet, B, Martin, G, Liger, D, Lovric, S, Furlano, M, Guerrera, IC, Sanchez-Ferras, O, Hu, JF, Boschat, AC, Sanquer, S, Menten, B, Vergult, S, De Rocker, N, Airik, M, Hermle, T, Shril, S, Widmeier, E, Yung Gee, H, Choi, WI, Sadowski, CE, Pabst, WL, Warejko, JK, Daga, A, Basta, T, Matejas, V, Scharmann, K, Kienast, SD, Behnam, B, Beeson, B, Begtrup, A, Bruce, M, Ch'Ng, GS, Lin, SP, Chang, JH, Chen, CH, Cho, MT, Gaffney, PM, Gipson, PE, Hsu, CH, Kari, JA, Ke, YY, Kiraly-Borri, C, Lai, WM, Lemyre, E, Littlejohn, RO, Masri, A, Moghtaderi, M, Nakamura, K, Ozaltin, F, Praet, M, Prasad, C, Prytula, A, Roeder, ER, Rump, P, Schnur, RE, Shiihara, T, Sinha, MD, Soliman, NA, Soulami, K, Sweetser, DA, Tsai, WH, Tsai, JD, Topaloglu, R, Vester, U, Viskochil, DH, Vatanavicharn, N, Waxler, JL, Wierenga, KJ, Wolf, MTF, Wong, SN, Leidel, SA, Truglio, G, Dedon, PC, Poduri, A, Mane, S, Lifton, RP, Bouchard, M, Kannu, P, Chitayat, D, Magen, D, Callewaert, B, Van Tilbeurgh, H, Zenker, M, Antignac, C & Hildebrandt, F 2017, 'Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly', Nature Genetics, vol. 49, no. 10, pp. 1529-1538. https://doi.org/10.1038/ng.3933
Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W et al. Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly. Nature Genetics. 2017 Oct 1;49(10):1529-1538. https://doi.org/10.1038/ng.3933
Braun, Daniela A. ; Rao, Jia ; Mollet, Geraldine ; Schapiro, David ; Daugeron, Marie Claire ; Tan, Weizhen ; Gribouval, Olivier ; Boyer, Olivia ; Revy, Patrick ; Jobst-Schwan, Tilman ; Schmidt, Johanna Magdalena ; Lawson, Jennifer A. ; Schanze, Denny ; Ashraf, Shazia ; Ullmann, Jeremy F.P. ; Hoogstraten, Charlotte A. ; Boddaert, Nathalie ; Collinet, Bruno ; Martin, Gaelle ; Liger, Dominique ; Lovric, Svjetlana ; Furlano, Monica ; Guerrera, I. Chiara ; Sanchez-Ferras, Oraly ; Hu, Jennifer F. ; Boschat, Anne Claire ; Sanquer, Sylvia ; Menten, Björn ; Vergult, Sarah ; De Rocker, Nina ; Airik, Merlin ; Hermle, Tobias ; Shril, Shirlee ; Widmeier, Eugen ; Yung Gee, Heon ; Choi, Won Il ; Sadowski, Carolin E. ; Pabst, Werner L. ; Warejko, Jillian K. ; Daga, Ankana ; Basta, Tamara ; Matejas, Verena ; Scharmann, Karin ; Kienast, Sandra D. ; Behnam, Babak ; Beeson, Brendan ; Begtrup, Amber ; Bruce, Malcolm ; Ch'Ng, Gaik Siew ; Lin, Shuan Pei ; Chang, Jui Hsing ; Chen, Chao Huei ; Cho, Megan T. ; Gaffney, Patrick M. ; Gipson, Patrick E. ; Hsu, Chyong Hsin ; Kari, Jameela A. ; Ke, Yu Yuan ; Kiraly-Borri, Cathy ; Lai, Wai Ming ; Lemyre, Emmanuelle ; Littlejohn, Rebecca Okashah ; Masri, Amira ; Moghtaderi, Mastaneh ; Nakamura, Kazuyuki ; Ozaltin, Fatih ; Praet, Marleen ; Prasad, Chitra ; Prytula, Agnieszka ; Roeder, Elizabeth R. ; Rump, Patrick ; Schnur, Rhonda E. ; Shiihara, Takashi ; Sinha, Manish D. ; Soliman, Neveen A. ; Soulami, Kenza ; Sweetser, David A. ; Tsai, Wen Hui ; Tsai, Jeng Daw ; Topaloglu, Rezan ; Vester, Udo ; Viskochil, David H. ; Vatanavicharn, Nithiwat ; Waxler, Jessica L. ; Wierenga, Klaas J. ; Wolf, Matthias T.F. ; Wong, Sik Nin ; Leidel, Sebastian A. ; Truglio, Gessica ; Dedon, Peter C. ; Poduri, Annapurna ; Mane, Shrikant ; Lifton, Richard P. ; Bouchard, Maxime ; Kannu, Peter ; Chitayat, David ; Magen, Daniella ; Callewaert, Bert ; Van Tilbeurgh, Herman ; Zenker, Martin ; Antignac, Corinne ; Hildebrandt, Friedhelm. / Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly. In: Nature Genetics. 2017 ; Vol. 49, No. 10. pp. 1529-1538.
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abstract = "Galloway-Mowat syndrome (GAMOS) is an autosomalrecessive disease characterized by the combination of earlyonset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.",
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T1 - Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly

AU - Braun, Daniela A.

AU - Rao, Jia

AU - Mollet, Geraldine

AU - Schapiro, David

AU - Daugeron, Marie Claire

AU - Tan, Weizhen

AU - Gribouval, Olivier

AU - Boyer, Olivia

AU - Revy, Patrick

AU - Jobst-Schwan, Tilman

AU - Schmidt, Johanna Magdalena

AU - Lawson, Jennifer A.

AU - Schanze, Denny

AU - Ashraf, Shazia

AU - Ullmann, Jeremy F.P.

AU - Hoogstraten, Charlotte A.

AU - Boddaert, Nathalie

AU - Collinet, Bruno

AU - Martin, Gaelle

AU - Liger, Dominique

AU - Lovric, Svjetlana

AU - Furlano, Monica

AU - Guerrera, I. Chiara

AU - Sanchez-Ferras, Oraly

AU - Hu, Jennifer F.

AU - Boschat, Anne Claire

AU - Sanquer, Sylvia

AU - Menten, Björn

AU - Vergult, Sarah

AU - De Rocker, Nina

AU - Airik, Merlin

AU - Hermle, Tobias

AU - Shril, Shirlee

AU - Widmeier, Eugen

AU - Yung Gee, Heon

AU - Choi, Won Il

AU - Sadowski, Carolin E.

AU - Pabst, Werner L.

AU - Warejko, Jillian K.

AU - Daga, Ankana

AU - Basta, Tamara

AU - Matejas, Verena

AU - Scharmann, Karin

AU - Kienast, Sandra D.

AU - Behnam, Babak

AU - Beeson, Brendan

AU - Begtrup, Amber

AU - Bruce, Malcolm

AU - Ch'Ng, Gaik Siew

AU - Lin, Shuan Pei

AU - Chang, Jui Hsing

AU - Chen, Chao Huei

AU - Cho, Megan T.

AU - Gaffney, Patrick M.

AU - Gipson, Patrick E.

AU - Hsu, Chyong Hsin

AU - Kari, Jameela A.

AU - Ke, Yu Yuan

AU - Kiraly-Borri, Cathy

AU - Lai, Wai Ming

AU - Lemyre, Emmanuelle

AU - Littlejohn, Rebecca Okashah

AU - Masri, Amira

AU - Moghtaderi, Mastaneh

AU - Nakamura, Kazuyuki

AU - Ozaltin, Fatih

AU - Praet, Marleen

AU - Prasad, Chitra

AU - Prytula, Agnieszka

AU - Roeder, Elizabeth R.

AU - Rump, Patrick

AU - Schnur, Rhonda E.

AU - Shiihara, Takashi

AU - Sinha, Manish D.

AU - Soliman, Neveen A.

AU - Soulami, Kenza

AU - Sweetser, David A.

AU - Tsai, Wen Hui

AU - Tsai, Jeng Daw

AU - Topaloglu, Rezan

AU - Vester, Udo

AU - Viskochil, David H.

AU - Vatanavicharn, Nithiwat

AU - Waxler, Jessica L.

AU - Wierenga, Klaas J.

AU - Wolf, Matthias T.F.

AU - Wong, Sik Nin

AU - Leidel, Sebastian A.

AU - Truglio, Gessica

AU - Dedon, Peter C.

AU - Poduri, Annapurna

AU - Mane, Shrikant

AU - Lifton, Richard P.

AU - Bouchard, Maxime

AU - Kannu, Peter

AU - Chitayat, David

AU - Magen, Daniella

AU - Callewaert, Bert

AU - Van Tilbeurgh, Herman

AU - Zenker, Martin

AU - Antignac, Corinne

AU - Hildebrandt, Friedhelm

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Galloway-Mowat syndrome (GAMOS) is an autosomalrecessive disease characterized by the combination of earlyonset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

AB - Galloway-Mowat syndrome (GAMOS) is an autosomalrecessive disease characterized by the combination of earlyonset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

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